Article
Biochemistry & Molecular Biology
Qingdan Du, Yen-Hua Huang, Conan K. Wang, Quentin Kaas, David J. Craik
Summary: Cyclotides are a family of macrocyclic peptides with diverse bioactivities. Understanding the role of individual residues in their structure and function has been challenging, particularly for the bracelet subfamily. This study investigated the role of specific residues in bracelet cyclotides through mutagenesis, revealing their importance in maintaining structure, membrane binding, and cytotoxic activity. These findings provide valuable insights for future biotechnological applications of bracelet cyclotides.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Krit Charupanit, Varomyalin Tipmanee, Thana Sutthibutpong, Praopim Limsakul
Summary: This study utilized computational methods to construct the protein sequence space of PETase-PET binding energy and identified mutation sites and appropriate side-chain properties that could enhance PETase activity. Molecular dynamics simulations revealed that PETase variants with S238C or Q119F may improve PETase efficiency. The findings have important implications for protein engineering and PETase improvement.
Article
Biochemistry & Molecular Biology
Surekha Kanagarajan, Prabhu Dhamodharan, Nachiappan Mutharasappan, Sanjay Kumar Choubey, Prajisha Jayaprakash, Jayashree Biswal, Jeyakanthan Jeyaraman
Summary: The study focused on the structure and function of enzymes in the pyrimidine biosynthetic pathway, particularly the role of CAD enzymes in cellular mechanisms. Through molecular modeling and dynamics studies of CAD complexes, key residues impacting their binding mode and enzyme activity were identified.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Chemistry, Medicinal
Karina van den Broek, Matthias Epple, Lisa Sophie Kersten, Hubert Kuhn, Achim Zielesny
Summary: The study of cyclotide-induced membrane disruption using dissipative particle dynamics revealed that the interaction between cyclotides and membranes is influenced by factors such as cholesterol content and membrane composition. The hydrophobic patch surface area of cyclotides plays a crucial role in their activity, and substitutions of amino acid residues may lead to super-mutants. Cyclotide mixtures exhibit linearly additive bioactivities without significant sub- or over-additive effects.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Microbiology
Nathaniel D. M. Holman, Anthony J. Wilkinson, Margaret C. M. Smith
Summary: In this study, the structure and function of S. coelicolor Pmt were investigated by mutating highly conserved residues. The results showed that substitutions of certain conserved residues led to loss of Pmt function, highlighting the importance of residue conservation for enzyme activity.
Article
Neurosciences
Alexandra Tran-Van-Minh, Michel De Waard, Norbert Weiss
Summary: Voltage-gated calcium channels are crucial for regulating brain function by allowing calcium entry into neurons. The proper functioning of these channels relies on the co-assembly of a pore-forming subunit (Ca-v alpha(1)) with ancillary subunits, with Ca-v beta playing a vital role in regulating surface expression and gating of the channels. In this study, the importance of surface charged residues in Ca-v beta(3) in the regulation of Ca(v)2.1 channels was investigated, revealing their contribution to channel gating and suggesting additional contacts beyond the known interaction between Ca-v alpha(1) and Ca-v beta.
Article
Virology
Brandon E. K. Tan, Michael R. Beard, Nicholas S. Eyre
Summary: In this study, random point mutagenesis was used to identify residues within NS1 that are essential for its secretion. Ten point mutations were identified that corresponded with impaired NS1 secretion. Additional studies on two of these mutants, V220D and A248V, revealed that they prevented viral RNA replication and disrupted NS1 processing or maturation.
Article
Chemistry, Medicinal
Xin Xue, Ji-Bo Kang, Xiao Yang, Nan Li, Liang Chang, Juan Ji, Xiang-Kai Meng, Hai-Qing Zhang, Yue Zhong, Shao-Peng Yu, Wen-Yu Wu, Xiao-Long Wang, Nian-Guang Li, Shan-Liang Sun
Summary: The study identified key interaction points between HIF-1α and VHL, and successfully synthesized a series of new inhibitors for VHL/HIF-1α protein-protein interactions. These inhibitors showed improved binding affinity and stability in cellular assays.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Plant Sciences
Haining Huang, Chongkun Zuo, Yaqian Zhao, Shen Huang, Tongkai Wang, Min Zhu, Jia Li, Xiaorong Tao
Summary: Sw-5b is an effective resistance gene in tomato against TSWV, but mutations in the viral protein NSm can lead to resistance-breaking isolates. By mutagenizing specific amino acids in NSm21, key residues for Sw-5b recognition were determined, and improved mutants were engineered to provide effective resistance against field and potential RB TSWV isolates.
MOLECULAR PLANT PATHOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Amaresh Kumar Mohanty, Muthuvel Suresh Kumar
Summary: Dengue fever is an endemic virus-borne disease that can cause severe ailments. The NS2B-NS3 protease plays a crucial role in viral replication, and mutated NS2B can affect the activation of NS3 protease, potentially leading to the occurrence of dengue fever.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Biochemistry & Molecular Biology
Carlos Santolaria, Diego Velazquez, Marcel Albacar, Antonio Casamayor, Joaquin Arino
Summary: The function of the Ppz1 phosphatase in Saccharomyces cerevisiae is controlled by its inhibitory subunit Hal3. Hal3 is a moonlighting protein involved in the CoA biosynthetic pathway. Deletion or specific mutations in a region of Hal3's N-terminal extension compromise its function as a Ppz1 inhibitor without affecting its ability to interact with the phosphatase. The presence of a specific sequence explains the unexpected ability of Cab3 to regulate Ppz1 function in Candida albicans. This study contributes to our understanding of Ppz phosphatase regulation and its importance in pathogenic fungi.
Article
Cardiac & Cardiovascular Systems
Maggie Wang, Adekunle Alabi, Hong-mei Gu, Govind Gill, Ziyang Zhang, Suha Jarad, Xiao-dan Xia, Yishi Shen, Gui-qing Wang, Da-wei Zhang
Summary: This study investigates the determinants of MT1-MMP-induced LDLR cleavage in LDLR and MT1-MMP. The study finds that MT1-MMP does not require a specific cleavage site on LDLR, but an amino acid residue with a hydrophobic side chain at position 167 in the MT-loop is critical for MT1-MMP-induced LDLR cleavage.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Microbiology
Mariana Leandro, Leandro Andrade, Luciano Vespoli, Julia Moreira, Vivian Pimentel, Fabiano Soares, Lucas Passamani, Vanildo Silveira, Goncalo de Souza Filho
Summary: This study investigated the key mechanisms of resistance to osmotic stress in Gluconacetobacter diazotrophicus. Proteomics analysis identified regulatory pathways for osmotic adjustment, de novo saturated fatty acids biosynthesis, and uptake of nutrients, while mutagenesis analysis showed the essential role of specific proteins in osmotolerance. The findings shed light on the importance of cell envelope and extracytoplasmic proteins for osmotolerance in this osmotolerant bacterium.
RESEARCH IN MICROBIOLOGY
(2021)
Article
Chemistry, Organic
Yi Wolf Zhang, Nan Zheng, Danny Hung-Chieh Chou
Summary: Phage display is a useful tool for discovering therapeutic antibodies and proteins. This study developed a new method for displaying insulin-like peptides on M13 phage, addressing the challenges posed by insulin's complex structure. The method has potential for displaying other structurally complex proteins on phage.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Nicia Rosario-Ferreira, Alexandre M. J. J. Bonvin, Irina S. Moreira
Summary: Understanding protein-protein interactions is crucial in studying biomolecular assemblies. Hot-spot residues significantly impact the formation of protein-protein complexes. Recent research is focusing on AI techniques to replace traditional energy-based methodologies.
WILEY INTERDISCIPLINARY REVIEWS-COMPUTATIONAL MOLECULAR SCIENCE
(2022)
Article
Chemistry, Medicinal
Xiaopeng Zhu, Shuai Wang, Quentin Kaas, Jinpeng Yu, Yong Wu, Peta J. Harvey, Dongting Zhangsun, David J. Craik, Sulan Luo
Summary: The researchers characterized a novel alpha-conotoxin, LvIC, and its analogues to probe structure-activity relationships at the alpha 6 beta 4 nAChR. They found a potent and specific antagonist, [D1G,delta Q14]LvIC, which could potentially serve as a novel molecular probe to explore alpha 6 beta 4 nAChR-related neurophysiological and pharmacological functions.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemical Research Methods
Isabella R. Palombi, Nicole Lawrence, Andrew M. White, Caitlin L. Gare, David J. Craik, Brendan J. McMorran, Lara R. Malins
Summary: Targeted drug delivery with peptide-drug conjugates (PDCs) was investigated as an alternative antimalarial therapy. PDCs with low micromolar potency were developed by conjugating a synthetic peptide derived from an innate human defense molecule with the antimalarial drug primaquine (PQ). Various PDCs were designed to identify the optimal conjugation site and investigate linker length, hydrophilicity, and cleavability. Conjugation within a flexible spacer region of the peptide, with a cleavable linker to liberate the PQ cargo, was crucial for retaining the activity of both the peptide and drug.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Biochemical Research Methods
Qiushi Cao, Cheng Ge, Xuejie Wang, Peta J. Harvey, Zixuan Zhang, Yuan Ma, Xianghong Wang, Xinying Jia, Mehdi Mobli, David J. Craik, Tao Jiang, Jinbo Yang, Zhiqiang Wei, Yan Wang, Shan Chang, Rilei Yu
Summary: With the rise of multidrug-resistant bacteria, antimicrobial peptides (AMPs) have emerged as potential alternatives to traditional antibiotics for treating bacterial infections. However, traditional methods of discovering and designing AMPs are time-consuming and costly. This study utilized deep learning techniques, including sequence generative adversarial nets, bidirectional encoder representations from transformers, and multilayer perceptron, to design and identify AMPs. Six candidate AMPs were then screened and one of them, A-222, showed inhibition against both gram-positive and gram-negative bacteria. Structural analysis and subsequent structure-activity relationship studies led to the design of peptide analogs with increased activity against specific bacteria. Overall, deep learning holds great promise in accelerating the discovery of novel AMPs and could have significant implications in developing new antimicrobial treatments.
BRIEFINGS IN BIOINFORMATICS
(2023)
Review
Biochemistry & Molecular Biology
Xiaorong Liu, Sonia T. Henriques, David J. Craik, Lai Yue Chan
Summary: This article introduces Gomesin, a cationic antimicrobial peptide isolated from the haemocytes of the Brazilian tarantula Acanthoscurria gomesiana and can be chemically produced. Gomesin exhibits a range of biological activities against therapeutically relevant pathogens and has been used for drug design and development. The review provides an overview of the discovery, structure-activity relationships, mechanism of action, biological activity, and potential clinical applications of Gomesin.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Zitong Zhao, Teng Pan, Shen Chen, Peta J. Harvey, Jinghui Zhang, Xiao Li, Mengke Yang, Linhong Huang, Shoushi Wang, David J. Craik, Tao Jiang, Rilei Yu
Summary: mu-Conotoxin KIIIA is a selective blocker of sodium channels with strong inhibitory activity against Nav1.7. Its structural modification and synthesis are challenging due to the presence of three pairs of disulfide bonds. In this study, three KIIIA analogues with one disulfide bond deleted were designed and synthesized. Among them, analogue KIIIA-1 showed the highest inhibitory activity on hNav1.7. A computational model was used to determine its binding pattern to hNav1.7 and guide the design of second and third-generation analogues. Peptide 37, the most potent analogue, exhibited significantly improved inhibitory activity on hNav1.7 and demonstrated potent analgesic effects in an in vivo pain model.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Plant Sciences
Abhishek Bajpai, Mark A. Jackson, Yen-Hua Huang, Kuok Yap, Qingdan Du, Tevin Chui-Ying Chau, David J. Craik, Edward K. Gilding
Summary: Cyclotides are stable and cyclic mini-proteins found in plants, which have nematicidal and anthelmintic activities. Extracts from four major cyclotide-producing plants were tested for their nematicidal properties and were found to be effective against Caenorhabditis elegans. The isolated cyclotides caused damage to the worms' mouth, pharynx, and midgut or membrane, and membrane disruption was implicated in their toxicity and death. The results provide a simple assay design to explore the nematicidal activities of plant extracts and purified cyclotides on C. elegans.
JOURNAL OF NATURAL PRODUCTS
(2023)
Review
Chemistry, Medicinal
Linh T. T. Nguyen, David J. J. Craik, Quentin Kaas
Summary: The venom of marine cone snails contains peptide toxins known as conopeptides, particularly conotoxins that are rich in disulfide bonds. Previous publications have mentioned the significant interest in conopeptides due to their potent and selective activity, but there has not been a formal analysis quantifying the popularity of the field. In this study, we conducted a bibliometric analysis of cone snail toxin literature from 2000 to 2022, which revealed the prolific nature of conopeptide research, with an average of 130 research articles per year.
Article
Biochemistry & Molecular Biology
Marie Morin, Mathias Joesson, Conan K. Wang, David J. Craik, Sandie M. Degnan, Bernard M. Degnan
Summary: This study investigates the impact of captivity on the physiology and health of crown-of-thorns starfish by comparing gene expression in wild and captive individuals. The results show significant differences in gene expression between wild and captive starfish, with genes involved in oxidative stress and energy metabolism upregulated in captivity. This suggests that caution should be taken when extrapolating results from captive marine animals to their wild counterparts.
Review
Biochemistry & Molecular Biology
Tristan J. Tyler, Thomas Durek, David J. Craik
Summary: Bioactive peptides are a diverse group of molecules with varied structures and functions. However, their use as drug candidates has been limited due to inherent shortcomings, including short half-lives and poor cell permeability. This review explores the use of molecular engineering to insert bioactive sequences into constrained scaffolds with desired pharmaceutical properties. Specifically, the focus is on cyclic disulfide-rich scaffolds, either naturally derived or engineered, which are intrinsically stable and amenable to sequence modifications, making them privileged frameworks in drug design.
Editorial Material
Biochemistry & Molecular Biology
Conan K. Wang
Article
Biochemical Research Methods
Mark A. A. Jackson, Jing Xie, Linh T. T. Nguyen, Xiaohan Wang, Kuok Yap, Peta J. J. Harvey, Edward K. K. Gilding, David J. J. Craik
Summary: Multiple sclerosis (MS) is a debilitating disease that requires prolonged treatment. The experimental therapeutic [T20K]kB1, a mutant of a plant peptide, shows promise for oral dosing and stability due to its cyclic structure. This study demonstrates the production of [T20K]kB1 in the Nicotiana benthamiana plant, providing a sustainable and cost-effective production method for cyclotide-based therapeutics.
TRANSGENIC RESEARCH
(2023)
Article
Immunology
Zhian Chen, Yanfang Cui, Yin Yao, Bo Liu, Joseph Yunis, Xin Gao, Naiqi Wang, Pablo F. Canete, Zewen Kelvin Tuong, Hongjian Sun, Hao Wang, Siling Yang, Runli Wang, Yew Ann Leong, David Simon Davis, Jiahuan Qin, Kaili Liang, Jun Deng, Conan K. Wang, Yen-Hua Huang, Jonathan A. Roco, Sam Nettelfield, Huaming Zhu, Huajun Xu, Zhijia Yu, David Craik, Zheng Liu, Hai Qi, Christopher Parish, Di Yu
Summary: In antibody responses, mutated germinal center B (BGc) cells are positively selected for reentry or differentiation, with the support of TFH cell-derived signals including CD40 and IL-21. The binding and signaling of IL-21 in BGc cells is reduced compared to non-BGc cells, due to low cellular heparan sulfate (HS) sulfation. Ndst1-mediated N-sulfation of HS in B cells promotes IL-21 binding and signal strength, and selective desensitization to IL-21 occurs in BGc cells. Therefore, the biochemical regulation of IL-21 availability and signal strength plays a crucial role in GC selection.
SCIENCE IMMUNOLOGY
(2023)
Article
Chemistry, Medicinal
Edin Muratspahic, Despoina Aslanoglou, Andrew M. White, Claudia Draxler, Xaver Kozisek, Zara Farooq, David J. Craik, Peter J. McCormick, Thomas Durek, Christian W. Gruber
Summary: In this study, peptide ligands for MC4R were designed using a peptide drug design approach. The designed peptides fully activated MC4R and recruited beta-arrestin-2 with higher efficacies and potencies than the endogenous alpha-MSH. These findings suggest the potential of these novel peptide ligands in developing safer and more effective antiobesity drugs.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2023)
Article
Microbiology
Nicole L. van der Weerden, Kathy Parisi, James A. Mckenna, Brigitte M. Hayes, Peta J. Harvey, Pedro Quimbar, Sean R. Wevrett, Prem K. Veneer, Owen Mccorkelle, Shaily Vasa, Rosemary Guarino, Simon Poon, Yolanda M. Gaspar, Michael J. Baker, David J. Craik, Rob B. Turner, Marc B. Brown, Mark R. Bleackley, Marilyn A. Anderson
Summary: Onychomycosis, or fungal nail infection, can cause pain, discomfort, and psychological and social consequences. Current treatments are limited by poor nail penetration or potential toxicity. Plant defensins, such as Ppdef1, have stable structures and potent antifungal activity, making them promising treatments. Ppdef1 shows excellent activity against a range of fungal pathogens, including Trichophyton rubrum, the major cause of onychomycosis.